Psoriasis is a chronic, uncurable multisystem inflammatory disease affecting skin and joints and leading to numerous complications. Symptomatic relief is available, but treatments, including biologicals, are compromised by safety and other issues, suggesting a need for improved therapies. Psoriasis is driven by immune cell-derived proinflammatory cytokines that cause uncontrolled keratinocyte proliferation; these cytokines can be induced by TNF, and TNF blocking antibodies such as adalimumab are approved for chronic plaque psoriasis. In addition, T helper (Th)17 cells produce IL-17A and IL-17F, which also activate keratinocyte proliferation. Accordingly, the anti-IL17A antibody secukinumab is approved for psoriasis. Thus, suppression of TH17 differentiation and/or IL- 17 signaling is a validated therapeutic approach for treating the underlying causes of psoriasis. The ubiquitin proteasome pathway is a primary regulator of immune function; the Nedd4-family E3 ligase Itch, which negatively regulates inflammatory responses, is a validated target for inflammation. Genetic ablation of Itch leads to multisystem immune disorders. The ligase is normally autoinhibited but is activated by the adapter protein Ndfip1. Ndfip1-/- mice develop inflammatory disease similarly to Itch-/- mice. Recently, Dr. Venuprasad Poojary?s laboratory discovered that Itch causes proteasomal degradation of the lineage specific transcription factor ROR- ?T, thereby suppressing Th17 differentiation and IL-17 production. Itch-/- mice develop spontaneous colitis and exhibit elevated IL-17 levels. Thus, Itch is a master negative regulator of inflammatory responses and its activation should provide therapeutic benefit. Progenra recently discovered small molecule Itch activators, and subsequent lead optimization has identified distinct chemical scaffolds (P053506 and P243876) that selectively activate Itch and impair cytokine production by T-cells. Moreover, they suppress IL-17 mRNAlevels in Th17 cells. It is proposed here to develop small molecule Itch activators as oral agents to limit TH17 differentiation and cytokine production, ultimately dampening the inflammatory responses in in vivo models of psoriasis and potentially having utility to treat severe to moderate psoriasis. In Phase I, the effect of selective Itch activators on Th17 cell differentiation, IL-17 production, and ROR-?T protein levels will be determined, and candidate activators will be evaluated for pharmacokinetics and oral bioavailability. The Imiquimod induced murine psoriasis model will be employed to determine in vivo efficacy. In Phase II, lead development and preclinical evaluation will continue using clinically relevant animal models. A successful project will lead to novel small molecule agents that can be used alone or in combination to treat psoriasis and other inflammatory diseases.